Associations of the Intellectual Disability Gene MYT1L with Helix–Loop–Helix Gene Expression, Hippocampus Volume and Hippocampus Activation During Memory Retrieval

Agnieszka Kepa (1) , Lourdes Martinez Medina (1) , Susanne Erk (2) , Deepak P Srivastava (1) , Alinda Fernandes (1) , Roberto Toro (3, 4) , Sabine Lévi (5) , Barbara Ruggeri (1) , Cathy Fernandes (1) , Franziska A. Degenhardt (6) , Stephanie H. Witt (7) , Andreas Meyer-Lindenberg (8) , Jean-Christophe Poncer (5) , Jean-Luc Martinot (9) , Marie-Laure Paillère Martinot (9, 10) , Christian Muller (11) , Andreas Heinz (2) , Henrik Walter (2) , Gunter Schumann (1) , Sylvane Desrivières (1)

1 Institute of Psychiatry, Psychology & Neuroscience, King's College London
2 Charité - UniversitätsMedizin = Charité - University Hospital [Berlin]
3 GHFC (UMR_3571 / U-Pasteur_1) - Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions
4 CNRS - UMR3571 - Gènes, Synapses et Cognition
5 Institut du Fer à Moulin
6 Universität Bonn = University of Bonn
7 Universität Heidelberg [Heidelberg] = Heidelberg University
8 Central Institute of Mental Health [Mannheim]
9 U1000 - Neuroimagerie en psychiatrie
10 Maison de Solenn [CHU Cochin]
11 FAU - Friedrich-Alexander Universität Erlangen-Nürnberg = University of Erlangen-Nuremberg

The fundamental role of the brain-specific myelin transcription factor 1-like (MYT1L) gene in cases of intellectual disability and in the etiology of neurodevelopmental disorders is increasingly recognized. Yet, its function remains under-investigated. Here, we identify a network of helix–loop–helix (HLH) transcriptional regulators controlled by MYT1L, as indicated by our analyses in human neural stem cells and in the human brain. Using cell-based knockdown approaches and microarray analyses we found that (1) MYT1L is required for neuronal differentiation and identified ID1, a HLH inhibitor of premature neurogenesis, as a target. (2) Although MYT1L prevented expression of ID1, it induced expression of a large number of terminal differentiation genes. (3) Consistently, expression of MYT1L in the human brain coincided with neuronal maturation and inversely correlated with that of ID1 and ID3 throughout the lifespan. (4) Genetic polymorphisms that reduced expression of MYT1L in the hippocampus resulted in increased expression of ID1 and ID3, decreased levels of the proneural basic HLH (bHLH) transcriptional regulators TCF4 and NEUROD6 and decreased expression of genes involved in long-term potentiation and synaptic transmission, cancer and neurodegeneration. Furthermore, our neuroimaging analyses indicated that MYT1L expression associated with hippocampal volume and activation during episodic memory recall, as measured by blood-oxygen-level-dependent (BOLD) signals. Overall, our findings suggest that MYT1L influences memory-related processes by controlling a neuronal proliferation/differentiation switch of ID-bHLH factors.

Domaines: Sciences du Vivant [q-bio]

Agnieszka Kepa, Lourdes Martinez Medina, Susanne Erk, Deepak P Srivastava, Alinda Fernandes, et al.. Associations of the Intellectual Disability Gene MYT1L with Helix–Loop–Helix Gene Expression, Hippocampus Volume and Hippocampus Activation During Memory Retrieval. Neuropsychopharmacology, 2017, 42 (13), pp.2516-2526. ⟨10.1038/npp.2017.91⟩. ⟨pasteur-01967213⟩